1. Field of the Invention
The present invention relates to processes for forming particles including drugs in a solution, changing the bulk or surface properties of a drug particle, and/or microencapsulating drug particles, and compositions produced thereby. In some embodiments, the process described utilizes mechanical agitation, more specifically low-frequency sonication, under controlled conditions, which provides mild shear forces during forming and/or precipitation to control the particle growth and mixing properties. Particle size can range from <200 nanometers to greater than one millimeter, depending on the processing conditions and application. The process described can be used to form a drug particle suspension, dry a wet powder slurry or suspension, as well as to improve the surface properties of the particle through conditioning the structure of the particle or particle surface and/or annealing the particle or particle surface. Annealing or conditioning drug particles may be used to force an amorphous to crystalline transition, creating a more stable powder, or smooth a particle surface. In addition, the process can be used to microencapsulate particles by suspending the microparticles in a non-solvent including a coating material (such as a biodegradable polymer) under controlled process conditions. The powder compositions produced thereby possess improved properties including, but not limited to, improved flow and dispersibility, controlled bioadhesion, stability, resistance to moisture, dissolution/release profiles, and/or bioavailabilities. This process, and the compositions produced, provide significant advantages in the manufacture of pharmaceutical particulate formulations, as well as biomedical, diagnostic, and chromatography particulate compositions, where sensitive macromolecules, such as proteins or DNA, are involved that would be degraded using more rigorous processing conditions or temperatures.
2. Description of Related Art
Conventional particle formation methods by crystallization, solvent evaporation, and filtration are known. Particle size is often reduced through secondary processing such as milling, while particle size may be increased through granulation and spray-coating techniques. Unfortunately, for small nanoparticles and microparticles used for inhaled, nasal, injectable, oral, and topical delivery, the resulting particles are highly charged and very cohesive, reducing their manufacturability and delivery efficiency and subsequent therapeutic efficacy. Therefore, what is needed are improved methods for preparing particles that do not suffer these limitations, and that are useful in preparing particles with distinct particle sizes and surface properties to obtain a superior final product.
There has been substantial effort in the last decade to produce drug particles from 100 nanometers to a few microns because of their improved dissolution properties (especially with insoluble drugs) and ability to be absorbed more efficiently. Drug particles, such as nanoparticles and microparticles, are usually formed either by size reduction (dry or wet milling) (Liversidge, Cundy et al. 1992), spray-drying, precipitation upon addition of a non-solvent, gelling the drug/polymer upon changing the pH or addition of a precipitating ions (salts) (Woiszwillo, Brown et al. 1999), or complexing a drug with a polymer of an opposite charge. For polymeric nanospheres or microspheres formed by emulsion techniques, the interior core of the particle is gelled and hardened, followed by collection through filtration or centrifugation. Microencapsulated particles include small particles with a drug dispersed in a polymer, or covered with a thin layer of coating material surrounding a nanoparticle or microparticle core. Microencapsulated drug particles may include a drug core with a coating on the surface that is made from a polymer or other material with the desired surface properties, which may improve the adhesion properties to a biological surface, sustain the release of the drug in a biological system or protect a drug from degradation under low pH or enzymatic cleavage (such as in the stomach). These systems, however, tend to be characterized by poor reproducibility and scalability in manufacturing, low encapsulation efficiencies (for microencapsulated particles), damage/denaturation of the drug when it is a macromolecule due to the use of organic solvents and/or spray-drying (Cleland and Jones 1996; Cleland, Mac et al. 1997), and poor shelf-life (Niemi, Turakka et al. 1990; Bartus, Tracy et al. 1998; Na, Stevens et al. 1999; Williams and Hu 2000; Suzuki, Ogawa et al. 2001). An example of a drug particle microencapsulation process is also described in U.S. Pat. No. 6,406,745, which may be used to microencapsulate drug particles efficiently without the use of solvents or high temperatures that may damage the drug molecule or activity (Talton 2002).
Final dosage forms incorporating drug particle compositions, such as a tablet or a solution for injection, typically contain bulking agents and/or surface stabilizers that may be chemically or physically attached on the surface, or more simply physically mixed, to disperse effectively. Oral tablets and capsules, as well as inhaled dry-powders, typically incorporate at least one pharmaceutically acceptable water-soluble or water-dispersible excipient. Common agents are known in the art as carriers, dispersants, or generally excipients, which require additional mixing to obtain biological activity upon storage and administration of a final dosage form. Because of the inherently high electrostatic forces present in nanoparticles and microparticles, direct mixing with carrier particles, such as in dry-powder inhaled formulations, may be inefficient and result in low quality final products. For this reason, manufacturing of nanometer and micrometer size drug particles that include excipients before the bulk mixing phase to improve the dispersion properties are of great interest to produce an improved final product.
Several groups have also explored the use of single-component drug particle systems with bioadhesive polymers to improve particle or drug adhesion to cell membranes and enhance absorption. A variety of materials have been shown to be successful including celluloses, hydrogel polymers, polycarbophils, polyanhydrides, polyacrylic acids, alginates, gelatins, gums, and pectin. Adhesion may be affected by physical or mechanical bonds, secondary chemical bonds, and/or primary, ionic or covalent bonds, which can improve the adhesion of bulk dosage forms or single particles. Reports have also shown that the adhesiveness of polymers to mucin/epithelial surfaces may be improved with anionic polymers with a high charge density. In U.S. Pat. No. 6,428,814, bioadhesive nanoparticles consisting of active cores coated with cationic surface stabilizers are described, which suggest increased adhesion to mucosal surfaces, such as the gastrointestinal (GI) tract, for systemic drug delivery (Bosch, Cooper et al. 2002). In U.S. Pat. No. 6,235,313, bioadhesive polymers were identified that were used as matrices during particle formation, producing particle surfaces that retain the bioadhesive properties of the polymer while encapsulating drugs within the particle (Mathiowitz, Chickering et al. 2001). Use of metal ions on the particle surface has also been used to enhance the bioadhesive properties of a polymer to enhance the adhesion to a tissue surface, such as a mucosal membrane (Jacob and Mathiowitz 2002). Metal compounds which enhance the bioadhesive properties of a polymer, as well as aid in the incorporation/precipitation of proteins during microencapsulation, typically include metal oxides and hydroxides, including oxides of calcium, iron, copper and zinc. Sustained-release profiles can be achieved after oral administration of drugs, such as proteins, by inclusion of metal-salts as complexing agents, as well as polymer degradation modifiers and stabilizers, particularly zinc (Jacob and Mathiowitz 2002).
Delivery of discrete nanoparticles and microparticles have been investigated for inhalation, nasal, topical, ocular, buccal, and injectable delivery. Pulmonary delivery of low molecular-weight drugs, peptides/proteins, and gene-therapy agents for local or systemic therapies presents unique formulation challenges. Efficient and reproducible drug deposition to central sections of the lung, such as glucocorticoids for asthma therapies, and peripheral sections of the lung for systemic delivery, such as insulin for patients with diabetes, is difficult because of limitations involved in aerosolization, stability, and clearance of micron-sized liquid droplets and powders. Currently available delivery systems for the inhalation of drugs include metered-dose inhalers (MDI's), dry-powder inhalers (DPI's), and nebulizers. Inhaled delivery of small molecule drugs including beta-agonists, such as albuterol, and glucocorticoids, such as budesonide and fluticasone propionate, have been used clinically for decades where small portions (20-200 μg) of the packaged dose are deposited in the desired portions of the lung (typically 5-10%). New non-invasive inhaled therapies being developed, such as peptides and proteins intended for systemic delivery, have distinctive physicochemical properties that further complicate efficient delivery, as well as may require large ‘lung-doses’ in the order of 2-20 mg, i.e. insulin. Dry-powder formulations of macromolecules are of particular interest for inhaled therapies since their stability is higher in the dry-state. Unfortunately, current formulations and inhalers are inefficient with fine particle doses of 5-20% of total emitted dose and high dose-to-dose variability. Coupled with regulatory requirements that inhaler systems meter and aerosolize micronized (usually <5 μm) powders reproducibly and several therapies have narrow therapeutic windows, improved inhaler devices and powder processing techniques are necessary to efficiently deliver therapeutics through the pulmonary route.
Spray-drying has been recognized as a viable alternative for the production of drug particles of controlled size in a one-step process. Generally, spray-dried particles are spherical and often hollow, resulting in a powder with a low bulk density in comparison to the starting material. The major drawback of the spray-drying process is that, due to the rapid drying of liquid droplets, metastable, high-energy amorphous forms of therapeutic compounds that may crystallize over time (amorphous to crystalline transition) are formed that influence product performance. Improved aerosol efficiency can also be achieved by co-spray drying with excipients such as salts, poly-peptides, carbohydrates such as lactose, mannitol, or trehalose, and lipids such as lecithin or phosphatidyl choline (Patton, Foster et al. 1999; Foster, Kuo et al. 2001). Particles of insulin, α-1-antitrypsin, and β-interferon have all been successfully prepared by co-spray drying with excipients. Unfortunately, typical spray-drying techniques require high inlet temperatures to obtain unagglomerated powders with low moisture content, which deactivates portions (10-80%) of the final product and have limited shelf-life (Adler and Lee 1999; Stahl, Claesson et al. 2002). Co-spray drying with carbohydrates (glass stabilization), such as trehalose, also improves the shelf-life stability of the peptide or protein. Sugars have also been used extensively to improve stability of lyophilized protein formulations for injection. These formulations in the “glass state” remain stable for long periods of time when stored well below the glass transition temperature, Tg. Unfortunately, for pulmonary applications where delivery of a maximum powder dose is limited, the use of significant quantities of additional excipient required to achieve stable particles limits the amount of the therapeutic dose achievable.
Drug particles have also been prepared using Super Critical Fluid (SCF) condensation methods, which take advantage of phase transitions of mixtures above a critical temperature and pressure (Palakodaty and York 1999). In the SCF region, these mixtures exist as a single phase and possess the solvent power of liquids together with the mass transfer properties of gases. Carbon dioxide is the most commonly used SCF because it is non-toxic, non-flammable, inexpensive, and has a low critical temperature that allows operation under ambient conditions. Similar to spray-drying, SCF processing may involve aerosolization and rapid dispersion/extraction of the organic solvent. Temperature and pressure regulation, together with precise metering of flow rates, provides control over mixing, nucleation and particle formation (Hanna and York 2000). Water-soluble compounds, such as peptides and proteins, are more challenging for SCF processing as they are insoluble in organic solvents. Similar to spray-drying, protein stabilization using carbohydrates is required in order to retain activity. The resulting drug particles are highly crystalline and particle-size is controlled by regulating the fluid dynamic interactions, but production rate is typically slow and requires specialized equipment and experience.
Sonication of liquids may be used to produce high shear forces and cavitation at high frequencies (Suslick, Doktycz et al. 1990). Ultrasonic frequencies (20-22 kHz) are typically used to disrupt cell membranes to analyze cell components, in addition to cleaving DNA (Elsner and Lindblad 1989). Sonication has also been used to form microbubbles for imaging agents (David, J. et al. 1990) using viscous aqueous solutions of sorbitol or dextrose, as well as heat-sensitive proteins such as albumin, at lower frequencies (5 to 10 kHz). While these techniques illustrate the formation of particles from solution at high ultrasonic frequencies, the nature of these processes involve cavitation and formation of microbubbles at hundreds of degrees or higher, which denature the solutes, such as albumin, into an insoluble spherical bubble. While this technique is advantageous for the production of gas-filled bubbles for enhancing ultrasound imaging of vascular systems, the application of these conditions for forming therapeutic drug particle systems is limited.
Ultrasonic frequencies (20 kHz) have also been used to form polymeric strands with high crystallinity at room temperature (Kirby 1998). In an earlier related technique, varying the frequency range from 80 to 2,000 Hz for short periods of time was also found to crystallize polymer fibers from solution (Keller and Jenkins 1978). The formed polymer mass with high surface area was then removed and air-dried for further processing. None of these techniques, though, anticipate the use of low-frequency sonication (LFS) in the range of 1 to 1,000 hertz, in combination with vacuum drying, to form drug particles of controlled composition and particle size in a one-step process.